The propulsion of intestinal contents is dependent on the coordination of contraction and relaxation of the circular and longitudinal muscle of the gut. Our previous studies have examined in detail the peristaltic reflex which underlies propulsive activity, and have resulted in a model of the neuronal circuit that mediates this reflex in rat, guinea pig and human. Our recent studies have expanded the model by identifying the modulatory roles of NPY and GRP in ascending and descending pathways, by characterizing the sensory limb activated by chemical stimulation of the mucosa with short chain fatty acids, and by identifying the influence of inflammatory cytokines on the reflex. The model of the peristaltic reflex has been fully validated in the mouse colon, allowing us to use a variety of transgenic mice in each aim listed below. In the current proposal, we will examine two novel endogenous regulators of neural function: the neurotrophins BDNF and GDNF, and the endocannabinoids. The first aim is to characterize the physiological role of BDNF in modulating the sensory limb of the peristaltic reflex and to examine the autocrine and paracrine mechanisms by which BDNF acts to enhance the release of the sensory neurotransmitter, CGRP. The receptor type(s) and signaling pathways that mediate the actions of BDNF will be determined. The second aim will characterize the role of GDNF and Neurturin in regulating the motor limb of the peristaltic reflex by examining their effect on motor and modulatory neurotransmitters. The third aim will characterize the role of the endocannabinoids in modulating the sensory and motor limbs of the peristaltic reflex. The release of endocannabinoids during each phase of the reflex, the relative roles of the C, B-1 and VR-1 receptors in mediating the response to endocannabinoids, and the interaction between endocannabinoids and neurotrophins will be determined. We have done extensive preliminary studies in support of these three aims, and their completion will enhance our understanding of the peristaltic reflex.